Affordable Membrane Permeability Calculations: Permeation of Short-Chain Alcohols through Pure-Lipid Bilayers and a Mammalian Cell Membrane

Determination of membrane permeability to small molecules from first-principles represents a promising approach for screening lead compounds according to their permeation properties upstream in the drug discovery process and prior to their synthesis. Theoretical investigation of permeation events requires, at its core, a molecular model of the membrane, and the choice of this model impacts not only the predicted permeability but also its relation to the experimental measurements commonly performed in pharmaceutical settings with a variety of cell lines capable of mimicking intestinal passive permeation. Homogeneous single-lipid bilayers have traditionally been utilized in computer simulations of membrane permeability predictions due to the ease of sampling all the relevant configurations, as well as the availability of parameters for a range of components of the biological membrane. To assess the influence of the membrane heterogeneity on the permeability to small molecules, we have examined the permeation of ethanol in six different single-lipid bilayers and compared the computed free-energy and diffusivity profiles with those obtained using a mammalian cell membrane model consisting of 26 components. Our results suggest that the membrane permeability only mildly depends on the lipid composition, spanning only 1 order of magnitude between the small phosphoethanolamine and the large phosphocholine head groups, or the short, saturated lauryl and the long, unsaturated oleyl acyl chains, that is, nearly as close as current theoretical estimates can get to experiment. The staggering computer time required to obtain an accurate free-energy profile, devoid of hysteresis between the upper and the lower leaflets of the lipid bilayer, in excess of several microseconds, provides an impetus for the development of approximate routes for membrane permeability predictions. Here, we have modeled the free-energy profile underlying permeation by means of a series of free-energy perturbation calculations, whereby the substrate is reversibly coupled to its environment at fixed values in the direction normal to the lipid bilayer. The diffusivity profile is modeled based on the bulk self-diffusion of the permeant, and the membrane permeability is recovered without significant loss of accuracy. The proposed numerical approach can be seamlessly extended to the determination of the relative membrane permeability to alternate substrates, thereby allowing large sets of permeants to be screened at a fraction of the computational cost of a rigorous determination of their respective free-energy profile